When drafting the Indications and Usage section of pharmaceutical labels for new or currently approved prescription drugs and biological products, FDA’s Draft Guidance emphasizes keeping the section concise. In general, FDA recommends that the Indications and Usage section be “clear, concise, useful, and informative and, to the extent possible, consistent within and across drug and therapeutic classes.”
However, in certain scenarios, sponsors may benefit from expanding the Indications and Usage section to include cross-referenced clinical studies or limitations of use.
General Contents of Indications and Usage
The Indications and Usage section is designed to assist medical practitioners with the identification of appropriate therapies. A clear and concise section will also facilitate indication indexing in drug databases, helping practitioners to easily locate the drug in clinical decision making.
Under 21 CFR 201.56, 201.57, the Indications and Usage section should:
- Use scientifically valid and clinically relevant language that is understandable to healthcare practitioners,
- Reflect scientific evidence accurately, and
- Be concisely written, including only the information necessary to clearly relate the product’s approved use(s).
According to 21 CFR 201.57(c)(2), the Indications and Usage section should clearly state:
- The disease, condition, or symptoms for which the drug is approved, and
- Whether the drug is indicated to treat, prevent, mitigate, cure, or diagnose the disease, condition, or symptoms.
In general, the Indications and Usage section of the label should be formatted as follows:
[TRADENAME] is indicated for use in prevention/treatment/maintenance/reducing risk of X disease for patients with (1) characteristic Y and (2) patients with characteristic Z.
Typically, any other information would be placed in other sections of the label, including the Dosage and Administration, Warnings and Precautions, Contraindications, Clinical Studies, or Use in Specific Populations sections.
Other Relevant Indications and Usage Information
Certain scenarios may warrant additional information to be included in the Indications and Usage section. Sponsors may need to state the specific benefits of a drug that targets different components of a disease. For example, the Indications and Usage section for a drug indicated to treat insomnia should include whether the drug affects sleep maintenance, sleep onset, or both.
Or sponsors may need to state the specific benefits of a drug that targets endpoints that are not well established. For example, in outcome studies, if the overall effect is on a composite endpoint, the Indications and Usage section should identify the composite’s components (e.g., myocardial infarction, stroke, and cardiovascular death) and clearly state which benefit(s) the drug has been observed to convey.
The following approved labels provide examples of Indications and Usage sections containing additional relevant information outside of the general template:
TAXOTERE
Taxotere (docetaxel) is used for:
- Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC
- Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC
- Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer
- Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction
- Squamous Cell Carcinoma of the Head and Neck Cancer (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN
LATUDA
LATUDA (lurasidone hydrochloride) is indicated for the treatment of:
- Schizophrenia [see Clinical Studies (14.2)].
- Depressive Episodes associated with Bipolar I Disorder (bipolar depression), as monotherapy and as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2)].
KEYTRUDA
KEYTRUDA (pembrolizumab) is indicated*:
- in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous Non-Small Cell Lung Cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
- in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC.
- as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
- Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic. [see Dosage and Administration 2.1]
- as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. [see for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
- as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
*Excerpt from Indications and Usage section
Using Cross-References in Drug Labeling
As shown in the examples above, the Indications and Usage section may need to reference a different label section where the topic is discussed in greater detail.
According to FDA’s Final Guidance on Labeling for Human Prescription Drug and Biological Products, “Cross-referencing is encouraged, and in some cases required… because it refers the reader to more or related information on the topic and reduces the need to repeat detailed information about a similar issue in several different sections.”
The preferred format for a cross-reference is to end the Indications and Usage section with [see SECTION (numerical identifier)] in italics. For example:
MULTAQ® is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF) [see Clinical Studies (14)].
In using cross references, the label section containing the most relevant prescribing information should remain concise and should cross-reference those sections containing more detailed information.
If the detailed information is contained in more than one label section, the sections should cross-reference each other from the least detailed section to the most detailed section (and not typically vice versa). For instance, if the Indications and Usage section refers the reader to expanded information in the Clinical Studies section, the Clinical Studies section does not need to refer the reader back to the Indications and Usage section.
Cross-referencing within labeling is not to be used as a substitute for developing a complete and appropriate Indications and Usage section containing all required elements.
Including Limitations of Use
An important Limitation of Use could be listed in the Indications and Usage section and refer the reader to the label’s Warnings and Precautions section containing more detailed information supporting the limitation. For example, FDA presentations and examples suggest the use of Limitations of Use in the Indications and Usage Section to indicate that approval was granted under accelerated approval.
Under the Draft Guidance, Limitations of Use should be presented separately from the indication information within the Indications and Usage section.
Example of Limitations of Use within the Indications and Usage section:
XOFLUZA
XOFLUZA (baloxavir marboxil) is indicated for:
- Treatment of acute uncomplicated influenza in patients who have been symptomatic for no more than 48 hours and who are: - otherwise healthy adults and pediatric patients 5 years of age and older, OR - adults and pediatric patients 12 years of age and older who are at highrisk of developing influenza-related complications.
- Post-exposure prophylaxis of influenza in patients 5 years of age and older following contact with an individual who has influenza.
Limitations of Use
Influenza viruses change over time, and factors such as the virus type or subtype, emergence of resistance, or changes in viral virulence could diminish the clinical benefit of antiviral drugs. Consider available information on drug susceptibility patterns for circulating influenza virus strains when deciding whether to use XOFLUZA.
Cross-Referencing to Clinical Studies
When cross-referencing to the Clinical Studies section of the label, it is helpful to understand how study findings are summarized within that section. The Clinical Studies section should not imply or suggest indications or uses not stated in the Indications and Usage Section (21 CFR 201.57(c)(15)(i)). According to the Guidance for Industry on Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products — Content and Format, “Words or phrases that lack a commonly understood meaning (e.g., imprecise quantitative terms), are not easily defined, are vague, misleading, or promotional in tone should be avoided.”
In general, the Clinical Studies section will need to include more detail on study findings for certain indications, particularly when more detailed information will add to the practitioner’s understanding of how the drug should be used and its clinical effects. The Guidance contains a detailed discussion of when more or less detail regarding study findings should be included in the Clinical Studies section of the label (section III(A)(2)).
For example, a detailed summary of study findings in the Clinical Studies section may need to contain the following elements regarding Disposition of Subjects to the extent they add to the practitioners’ understanding of drug effectiveness:
- Number of subjects enrolled
- Number of subjects completing the study
- Number of subjects discontinuing the study / reasons for discontinuation
- For studies with run-in periods or other distinct phases, the number of subjects entering each phase and the number of subjects not progressing to the next phase. (section III(C)(1)).
Indications and Usage Labeling and Induced Infringement
Careful attention to the language applied in the Indications and Usage section and any cross-referenced sections is vital to proper Orange Book patent listing and facilitating patent enforcement, preventing infringement, and avoiding litigation.
Sanofi v. Watson Labs
In 2017, the U.S. Federal Circuit Court of Appeals held that the content of a label permitted the inference of specific intent to encourage infringing use (Sanofi v. Watson Labs. Inc. - 875 F.3d 636 (Fed. Cir. 2017)). In this case, pharmaceutical company Sanofi owned a patent describing and claiming compositions and uses of the antiarrhythmic drug dronedarone. The patent claimed a method of reducing risk of cardiovascular hospitalization by administering an effective amount of dronedarone to patients having a list of specified characteristics.
In 2009, a Sanofi subsidiary, Sanofi-Aventis U.S., LLC, received approval for an NDA for tablets of dronedarone, sold as Multaq®. The dronedarone patent was listed in the Orange Book as a method of using Multaq®.
The original 2009 Multaq® label Indications and Usage label read as follows:
MULTAQ® is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted [see Clinical Studies (14)].
Later, Watson Laboratories Inc. and Sandoz Inc. sought to market generic versions of Multaq®. They filed ANDAs and certified that they believed the generic drugs’ manufacture, sale, and use would not infringe the patent. Sanofi received notice of this paragraph IV certification and sued Watson and Sandoz for infringement.
The district court sided with Sanofi, holding that the defendants’ sale of the generics and their proposed labels would induce infringement. A Federal Circuit Court of Appeals affirmed the judgment .
Importantly, the appellate court held that the fact that Watson and Sandoz planned to market generic Multaq® using the same labeling and detailed criteria listed in Sanofi’s label suggests intent of inducement to infringe (citing Takeda v. West-Ward, 785 F.3d 625, 631 (Fed. Cir. 2015)).
The Federal Circuit opinion states, “Watson and Sandoz “kn[o]w that their proposed labels would actually cause physicians to prescribe dronedarone to patients with the cardiovascular risk factors claimed” and that “such a use would infringe the ’167 patent”. The opinion adds, “There was considerable testimony that this label encourages—and would be known by Watson and Sandoz to encourage—administration of the drug to those patients, thereby causing infringement.”
Specifically, the opinion explains:
“The label itself has a short “Indications and Usage” section, one sentence long. It states what dronedarone is indicated for: it “is indicated to reduce the risk of hospitalization for atrial fibrillation.” And it states which patients are covered by this indication: “patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF) [see Clinical Studies (14)].
The reference to the Clinical Studies section (14) of the label expressly directs the reader to that section for elaboration on the class of patients for whom the drug is indicated to achieve the stated objective, i.e., reduced hospitalization.
Section 14 leads with and features a subsection on the ATHENA study, which sets forth the positive results, relating to reduced hospitalization, for patients having the risk factors written into the ’167 patent. And it is only the ATHENA subsection— not any of the three other brief subsections—that identifies a class of patients as having been shown to achieve reduced hospitalization from use of dronedarone. The EURIDIS/ADONIS subsection says nothing about reduced hospitalization; and the ANDROMEDA and PALLAS subsections are negative warnings, describing studies that had to be terminated early because of adverse results. The label thus directs medical providers to information identifying the desired benefit for only patients with the patent-claimed risk factors.”
The cross-reference written as “[see Clinical Studies (14)]” included in the Indications and Usage section of the label played a critical role in Sanofi’s ability to prove induced infringement.
Vanda v. West-Ward
A similar case win can be seen in Vanda v West-Ward, 887 F.3d 1117 (Fed. Cir 2018).*In 2018, the Federal Circuit Court found induced infringement of a patent owned by Vanda Pharmaceuticals after West-Ward Pharmaceuticals used a similar label describing the clinical trial results.
Vanda owns an NDA for FANAPT® (iloperidone). In 2013, West-Ward filed an ANDA seeking approval to manufacture and sell generic iloperidone. While West-Ward’s ANDA was pending, Vanda listed a newly obtained patent—Patent ‘610: Methods For The Administration Of Iloperidone—in the Orange Book. In response, West-Ward amended its pending ANDA to certify that Vanda’s new method of use patent was invalid or not infringed.
Vanda sued West-Ward for inducing infringement of patent ‘610, asserting that West-Ward’s proposed product label would induce infringement. Among other defenses, West-Ward argued that the ‘610 patent contained ineligible subject matter and was therefore invalid. The District Court held that West-Ward induced infringement.
West-Ward appealed the decision. In addressing West-Ward’s claim of ineligible subject matter, the Federal Circuit focused the analysis on the proposed product labeling. Under 35 U.S.C. § 101, patent claims based on abstract ideas, laws of nature, or natural phenomena are considered patent ineligible. Vanda’s method of use patent claim included language regarding specific treatment steps and dosage ranges. Furthermore, the ‘610 patent expanded on the significance of those specific dosage ranges based on patient genotype.
The Federal Circuit found the Vanda’s claims patent eligible, stating:
“At bottom, the claims here are directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome… They recite more than the natural relationship between CYP2D6 metabolizer genotype and the risk of QTc prolongation. Instead, they recite a method of treating patients based on this relationship that makes iloperidone safer by lowering the risk of QTc prolongation.”
The court found that West-Ward’s proposed label was "substantially identical" to Vanda's label for FANAPT® and constituted an act of induced infringement. The Federal Circuit reasoned that “Even if not every practitioner will prescribe an infringing dose, that the target dose range instructs users to perform the patented method is sufficient to provide evidence of West-Ward’s affirmative intent to induce infringement.”
Prior to litigation, Vanda’s FANAPT label Indications and Usage section read as follows:
FANAPT is an atypical antipsychotic agent indicated for the acute treatment of schizophrenia in adults (1). In choosing among treatments, prescribers should consider the ability of FANAPT to prolong the QT interval and the use of other drugs first. Prescribers should also consider titrating FANAPT slowly to avoid orthostatic hypotension, which may lead to delayed effectiveness compared to other drugs that do not require similar titration.
Following the initiation of litigation, Vanda amended the Indications and Usage section to include cross-references. The new label reads as follows:
FANAPT® is indicated for the treatment of schizophrenia in adults. When deciding among the alternative treatments available for this condition, the prescriber should consider the finding that FANAPT is associated with prolongation of the QTc interval [see Warnings and Precautions (5.3)]. Prolongation of the QTc interval is associated with other drugs that can cause torsade de pointes-type arrhythmia. This potentially fatal polymorphic ventricular tachycardia can result in sudden death. In many cases, this would lead to the conclusion that other drugs should be tried first. Whether FANAPT will cause torsade de pointes or increase the rate of sudden death is not yet known. Patients must be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require a similar titration. Prescribers should be mindful of this delay when selecting an antipsychotic drug for the treatment of schizophrenia [see Dosage and Administration (2.1) and Clinical Studies (14)].
By including cross-references, the language of the revised label provides further protection against potential inducement to infringe, highlighting important aspects for potential competitors and legal advisors.
Important Considerations for Cross-Reference Use
Sponsors and applicants should evaluate the potential benefits of including cross-references when drafting the Indications and Usage section of pharmaceutical labels for new or currently approved prescription drugs and biological products. Similarly, applicants should pay close attention to the language applied in the Indications and Usage section and any cross-referenced sections when assessing patents for Orange Book listing and evaluating the potential for induced infringement.
* Although Pharmaceutical Law Group PC represents Vanda Pharmaceuticals in some regulatory matters, Pharmaceutical Law Group did not represent Vanda Pharmaceuticals on the issues raised in Vanda v West-Ward, 887 F.3d 1117 (Fed. Cir 2018).